Efficient lipid delivery to human tear film using a salt-sensitive emulsion system

ABSTRACT

A salt-free emulsion for the treatment of dry eye and other ocular conditions is disclosed which contains castor oil and does not contain olive oil which prolongs TBUT and provides superior comfort.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.Nos. 61/568,089, filed Dec. 7, 2011 and 61/625,401 filed Apr. 17, 2012,the disclosures of which are hereby incorporated in their entiretyherein by reference.

FIELD OF INVENTION

The present invention is directed to artificial tears suitable fortreating dry eye syndrome and other ocular conditions in a human orother mammal.

BACKGROUND OF THE INVENTION

Typical symptoms of keratoconjunctivitis or dry eye include feelings ofdryness, burning, and a sandy-gritty eye sensation that can worsenduring the day. Symptoms may also be described as itchy, scratchy,stingy or tired eyes. Other symptoms include pain, redness, a pullingsensation, and pressure behind the eye. The damage to the eye surfaceresulting from dry eye increases discomfort and sensitivity to brightlight and both eyes usually are affected.

Because blinking coats the eye with tears, symptoms are worsened byactivities in which the rate of blinking is reduced due to prolonged useof the eyes. These activities include prolonged reading, computer usage,driving or watching television. Symptoms increase in windy, dusty orsmoky areas, in dry environments, high altitudes including airplanes, ondays with low humidity, and in areas where an air conditioner, fan, orheater, is being used. Symptoms are less severe during cool, rainy, orfoggy weather, and in humid places. Most people who have dry eyesexperience mild irritation with no long-term effects. However, if thecondition is left untreated or becomes severe, it can producecomplications that can cause eye damage, resulting in impaired vision orpossibly in the loss of vision.

Having dry eyes for a prolonged period of time can lead to tinyabrasions on the surface of the eyes. In advanced cases, the epitheliumundergoes pathologic changes, namely squamous metaplasia and loss ofgoblet cells sometimes due to activation of T cells acting against thosecells. Some severe cases result in thickening of the corneal surface,corneal erosion, punctate keratopathy, epithelial defects, cornealulceration, corneal neovascularization, corneal scarring, cornealthinning, and even corneal perforation. An abnormality of any one of thethree layers of tears which produces an unstable tear film, may resultin symptoms of keratitis sicca.

Keratoconjunctivitis sicca is usually due to inadequate tear production.The aqueous tear layer is affected, resulting in aqueous tear deficiencyor lacrimal hyposecretion. The lacrimal gland does not producesufficient tears to keep the entire conjunctiva and cornea covered by acomplete layer. This usually occurs in people who are otherwise healthy.Increased age is associated with decreased tearing. This is the mostcommon type found in postmenopausal women. Causes include idiopathic,congenital alacrima, xerophthalmia, lacrimal gland ablation, and sensorydenervation. In rare cases, it may be a symptom of collagen vasculardiseases, including rheumatoid arthritis, Wegener's granulomatosis, andsystemic lupus erythematosus. Sjögren's syndrome and autoimmune diseasesassociated with Sjögren's syndrome are also conditions associated withaqueous tear deficiency. Drugs such as isotretinoin, sedatives,diuretics, tricyclic antidepressants, antihypertensives, oralcontraceptives, antihistamines, nasal decongestants, beta-blockers,phenothiazines, atropine, and pain relieving opiates such as morphinecan cause or worsen this condition. Infiltration of the lacrimal glandsby sarcoidosis or tumors, or postradiation fibrosis of the lacrimalglands can also cause this condition.

Keratoconjunctivitis sicca can also be caused by abnormal tearcomposition resulting in rapid evaporation or premature destruction ofthe tears. When caused by rapid evaporation, it is termed evaporativedry eyes. In this condition, although the tear gland produces asufficient amount of tears, the rate of evaporation of the tears is toorapid. There is a loss of water from the tears that results in tearsthat are too “salty” or hypertonic. As a result, the entire conjunctivaand cornea cannot be kept covered with a complete layer of tears duringcertain activities or in certain environments.

Aging is one of the most common causes of dry eyes. This is due to thefact that tear production decreases with age. It may be caused bythermal or chemical burns, or by adenoviruses. Diabetics are also atincreased risk for dry eye.

An eye injury or other problem with the eyes or eyelids, such as bulgingeyes or a drooping eyelid, can cause keratoconjunctivitis sicca.Disorders of the eyelid can impair the complex blinking motion requiredto spread tears.

About half of all people who wear contact lenses have dry eyes. This isbecause soft contact lenses, which float on the tear film that coversthe cornea, absorb the tears in the eyes. Dry eye also occurs or getsworse after refractive surgeries, in which the corneal nerves are cutduring the creation of a corneal flap, because the corneal nervesstimulate tear secretion. Dry eyes caused by these procedures usuallydisappear after several months.

Abnormalities of the lipid tear layer caused by blepharitis and rosaceaand abnormalities of the mucin tear layer caused by vitamin Adeficiency, trachoma, diphtheric keratoconjunctivitis mucocutaneousdisorders and certain topical medications may cause dry eye orkeratoconjunctivitis sicca.

Dry eyes can usually be diagnosed by the symptoms alone. Tests candetermine both the quantity and the quality of the tears. A slit lampexamination can be performed to diagnose dry eyes and to document anydamage to the eye. A Schirmer's test can measure the amount of moisturebathing the eye. This test is useful for determining the severity of thecondition.

A variety of approaches can be taken to treatment, such as: avoidance ofexacerbating factors, tear stimulation and supplementation, increasingtear retention, and eyelid cleansing and treatment of eye inflammation.For mild and moderate cases, supplemental lubrication is the mostimportant part of treatment. Application of artificial tears every fewhours can provide temporary relief.

Lubricating tear ointments can be used during the day, but theygenerally are used at bedtime due to poor vision after application. Theycontain white petrolatum, mineral oil, and similar lubricants. Theyserve as a lubricant and an emollient. Depending on the severity of thecondition, ointments may be applied from every hour to just at bedtime.Ointments should not be used with contact lenses. Inflammation occurringin response to tears film hypertonicity can be suppressed by mildtopical steroids or with topical immunosuppressants such ascyclosporine.

SUMMARY OF THE INVENTION

The present invention is comprised of an artificial tear emulsion of thefollowing formulation:

TABLE I [1] POLYSORBATE 80 0.5 % w/w Active Grade: NF Ph Eur [2]CARBOXYMETHYL- 0.5 % w/w Active CELLULOSE SODIUM (LOW VISCOSITY 7LFPH)Grade: Ph Eur USP [3] GLYCERIN 1.0 % w/w Active Grade: Ph Eur USP [4]PURITE 0.01 % w/w Preservative Grade: BORIC ACID 0.6 % w/w Buffer Grade:NF Ph Eur [5] PEMULEN TR-2 0.1 % w/w Stabilizer Grade: NF [6] CASTOR OIL0.25 % w/w Excipient Grade: Eur Ph USP ERYTHRITOL 0.25 % w/w ExcipientGrade: NF Ph Eur LEVOCARNITINE 0.25 % w/w Excipient Grade: Ph Eur USP[7] SODIUM HYDROXIDE 7.3 pH pH Adjust Grade: NF Ph Eur [8] WATER FORINJECTION/ 100 % w/w QS Adjust PURIFIED WATER Grade: USP [1] PM# 12783.Super Refined Polysorbate 80 from CRODA. Primary emulsifer anddemulcent. [2] Demulcent [3] Demulcent and tonicity agent [4] StabilizedOxychloro Complex (Purite). Add by assay value. [5] Pemulen TR-2NF(Carbomer Copolymer Type A, Tested to Ph Eur). Secondary emulsifer. [6]Lipophilic vehicle [7] pH target 7.3 [8] Hydrophilic vehicle

The Table I formulation includes the concentrations of actives and/orexcipients as disclosed above which can be in concentrations which varyfrom what is stated above. The variation may be such that the amountsare “about” what is stated above so long as that amount would be foundbioequivalent by a regulatory agency such as the FDA or the EMEA.

The formulation may be preserved or non-preserved (not containingPurite®), such as a unit dose version. This version would be the same asthat in Table 1 except it would contain no Purite®.

Some embodiments of the invention are included in the followingparagraphs:

-   1) A composition useful as an artificial tear, which is a salt free    emulsion comprising castor oil and specifically excludes olive oil    and contains at least one active agent selected from the group    consisting of polysorbate, carboxymethylcellulose and glycerine.-   2) The composition of paragraph 1 wherein said mixture comprises    from about 0.1% -0.5% w/w, castor oil.-   3) The composition of paragraphs 1-2 wherein castor oil is the only    oil in the emulsion.-   4) The composition of paragraphs 1-3 wherein the castor oil is    emulsified in an aqueous phase.-   5) The composition of paragraph 4 wherein the castor oil is present    in about 0.25% w/w .-   6) The composition of paragraphs 4-5 further including a primary and    a secondary emulsifier.-   7) The composition of paragraphs 1-6 wherein the composition    contains a preservative.-   8) The composition of paragraph 7 wherein the preservative is    selected from the group consisting of PURITE and benzalkoniuim    chloride.-   11. The composition of paragraph 8 wherein the preservative is    PURITE is present in a concentration of about 0.01% w/v.-   12. An emulsion for use in treating dry eye wherein the emulsion is    salt-free and comprises castor oil, polysorbate 80,    carboxymethylcellulose and glycerine.-   13. The composition of paragraph 12 wherein the emulsion also    contains the emulsifier pemulin.-   14. The emulsion of paragraphs 12-13 further comprising erythritol    and levocarnitine.-   15. An emulsion for treating dry eye as shown in Table 1.-   16. A method of treating dry eye comprising administration of any    one of the compositions or emulsions of paragraphs 1-15.-   17. A composition for the treatment of dry eye or    keratoconjunctivitis sicca wherein the composition comprises about    0.5% w/w Polysorbate 80, about 0.5% w/w carboxymethylcellulose,    about 1.0% w/w glycerine, about 0.6% w/w boric acid, about 0.1% w/w    pemulin, about 0.25% w/w castor oil, about 0.25% w/w erythritol,    about 0.25% w/w levocarnitine, sodium hydroxide to adjust the pH to    about 7.3 and water.-   18. The composition of claim 17 further comprising 0.01% Purite®.-   19. The composition of claim 17 wherein the composition is applied    topically to an eye which is suffering from dry eye.-   20. The composition of claim 17 wherein the composition is applied    topically to an eye to alleviate the symptoms of dry eye.-   21. The composition of claim 17 wherein the composition is applied    topically to an eye to prevent dry eye syndrome.

As used herein, the term “effective amount” or “effective dose” means anamount sufficient to achieve the desired result on the process orcondition, and it accordingly will depend on the ingredient and thedesired result. Nonetheless, once the desired effect is known,determining the effective amount is within the skill of a person skilledin the art.

“Formulation,” “composition,” and “preparation” as used herein areequivalent terms referring to a composition of matter suitable forpharmaceutical use (i.e., producing a therapeutic effect as well aspossessing acceptable pharmacokinetic and toxicological properties).

The term “prevent” as used herein refers to a decrease in the occurrenceof dermatological symptoms (e.g., urticardial wheals) in a patient. Theprevention may be complete (i.e., no detectable symptoms) or partial, sothat fewer symptoms are observed than would likely occur absenttreatment.

As used herein, the terms “prevent” and “treat” are not intended to beabsolute terms. Treatment can refer to any delay in onset, e.g.,reduction in the frequency or severity of symptoms, amelioration ofsymptoms, improvement in patient comfort, reduction in symptoms of dryeye, and the like. The effect of treatment can be compared to anindividual or pool of individuals not receiving a given treatment, or tothe same patient before, or after cessation of, treatment.

The term “therapeutically effective amount” as used herein refers tothat amount of the composition or agent in a composition sufficient toameliorate one or more aspects of the disorder.

Therapeutic efficacy can also be expressed as “-fold” increase ordecrease. For example, a therapeutically effective amount can have atleast a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over acontrol.

“Treatment” as used herein includes any cure, amelioration, orprevention of a disease. Treatment may prevent the disease fromoccurring; inhibit the disease's spread; relieve the disease's symptomsfully or partially remove the disease's underlying cause, shorten adisease's duration, or do a combination of the above. “Treating” or“treatment” as used herein (and as well-understood in the art) alsobroadly includes any approach for obtaining beneficial or desiredresults in a subject's condition, including clinical results. Beneficialor desired clinical results can include, but are not limited to,alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delay or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable.

“Treating” and “treatment” as used herein may include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of an active agent. The administeringstep may consist of a single administration or may include a series ofadministrations. The length of the treatment period depends on a varietyof factors, such as the severity of the condition, the age of thepatient, the concentration of active agent, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

DETAILED DESCRIPTION OF THE INVENTION

Delivering lipids to the human tear film to supplement and enhance thenative lipid layer, often deficient due to dysfunction of meibomianglands and other causes, is a recognized strategy in treating signs andsymptoms of dry eye. This is in theory especially beneficial in lowhumidity or when other internal/external factors increase tear filmevaporation. Excessive loss of water from the tear film causes anincrease in salt content and causes hyperosmotic stress to the cells ofthe ocular surface.

The native lipid layer is very thin and the total volume of lipid is asmall fraction of the total tear film volume. To enhance the structureand function of the lipid layer by topical application of alipid-containing drop requires only a small volume of oil to bedelivered; excess lipid will displace and disrupt the total aqueousvolume, by far the greatest component of tears. It is also necessarythat the lipid be delivered quickly, during the brief contact time of atopical eye drop. Finally, the lipid delivered needs to becomeestablished as part of the native lipid layer, at the air interface.

The challenge of lipid release from an emulsion has been approached byusing substantial amounts of lipid (1-5%) and/or building an emulsionsystem that readily separates. The disadvantage of this approachincludes: the product requires shaking, the clarity of the emulsion isgreatly reduced, the total volume of lipid delivered to the eye ispotentially large and variable and tolerability can be lower than anfully aqueous eye drop.

An alternate means of lipid release involves the use of a salt-sensitiveemulsion system in a product intended for topical use that is largelyfree of salt. This system uses a surfactant and viscosity-increasingpolymer to hold the lipid (eg. castor oil) in a stable sub-micronemulsion. When mixed with human tear, the natural salt content (oftenfurther elevated in dry eye) is sufficient to rapidly cause a drop inproduct viscosity due to action on the polymer structure. This loss ofviscosity allows lipid release to occur to a significantly greaterdegree and much faster.

Efficiency of lipid delivery can be defined as the amount of lipidreleased from the emulsion, as a proportion of total lipid content, overtime under standard test conditions.

Efficiency of lipid delivery in the presence of salt is supported, forexample, using simple laboratory methods. Specifically, when dilutedwith water, this system shows a loss of viscosity proportional to watervolume added. When exposed to salt (NaCl) by mixing 1:1 with even a weaksaline solution (30 mOsm) a loss of viscosity of over 60% occurs vs. 50%when mixed with water. Higher saline strength (up to about 600 mOsm)caused significantly greater loss of viscosity, confirming action ofsalt on polymer structure.

The release of lipid was demonstrated using a controlled centrifuge withreal-time integrated optical detector (Lumisizer). During 2 minutes of4000 RPM stress, uniformity of the emulsion was confirmed by equivalentoptical transmission from bottom to top of the centrifuge sample holderfor both full strength and water-diluted product. However, diluting theproduct with saline (volume and concentration replicating on-eye use)showed a clear and remarkable change in product uniformity consistentwith lipid release and migration to the top of the sample holder,consistent with “floating” to the air interface. Surprisingly andbeneficially, this may occur without coalescence (no increase in averagelipid droplet size) allowing the lipid to mix into the native layer moreeffectively. Average particle (lipid droplet size) was unchanged whensaline was added (Horiba)

Clinical results have confirmed that the new lipid emulsion system workseffectively in prolonging TBUT (tear break-up time) yet demonstratestolerability and comfort improvements vs. an emulsion more optimized fordrug delivery.

The benefits of using a salt-sensitive emulsion system as shown in TableI, that is largely free of salts, include but are not limited to:

-   -   1) No need to shake the product—excellent in bottle stability        and uniformity;    -   2) Efficient delivery of lipid on eye due to the salt-induced        decrease in viscosity and destabilization of emulsion structure        enabling more efficient lipid release;    -   3) Improved tolerability by lowering total lipid content;    -   4) Effective stabilization and supplementation of the native        lipid layer; and    -   5) Possibly greater delivery of beneficial lipid in patients        with higher tear salt content, a so-called “smart” vehicle.

The incorporation of osmoprotectants (1-carnitine and erythritol) andhumectants/lubricants (glycerin and carboxymethylcellulose increases theclinical usefulness of this product to a broader range of dry eyepatients than other emulsion systems targeting lipid deficiency ormeibomian gland dysfunction.

EXAMPLE 1 A Multicenter, Investigator-masked, Randomized, 4-Arm,Parallel-group Study to Evaluate the Safety, Efficacy, and Acceptabilityof a Unit-dose Eye Drop Formulation in Subjects With Dry Eye Disease

The objective of the study was to evaluate the safety, efficacy, andacceptability of the formulation of Table 1, but without containingPurite®, referred to as a Next Generation Emulsion Unit-dose or (“NGEUD”) in subjects with signs and symptoms of dry eye disease.

Methodology

This was a multicenter, investigator-masked, randomized,active-controlled, 4-arm, parallel group study designed to compare thesafety, efficacy, and acceptability of NGE UD to commercially availableOPTIVE™ Sensitive Preservative-free Lubricant Eye Drops Unit-dose(“OPTIVE UD”), NGE UD to Next Generation Emulsion Multidose (“NGE MD”)(same formulation as Table 1 but with Purite®), and NGE MD to OPTIVE™Lubricant Eye Drops Multidose (“OPTIVE MD”).

The planned study duration was 30 days for each subject and consisted ofup to 3 scheduled visits (days 1 [baseline], 7, and 30 [exit]). On day1, eligible subjects with signs and symptoms of dry eye disease wereassigned according to a 2:2:1:1 treatment allocation ratio to use NGEUD, OPTIVE UD, NGE MD, or OPTIVE MD, respectively. The studyrandomization was stratified by baseline Ocular Surface Disease Index©(OSDI) score (mild/moderate symptoms=score of 18 to 32; severesymptoms=score of >32 to 65). Approximately 300 subjects were to beenrolled at 13 to 14 sites within the USA in order to have 288 completedsubjects assuming a dropout rate of approximately 5%. Subjects wereinstructed to instill 1 to 2 drops of their assigned study product ineach eye, as needed, but at least 2 times daily for 30 days.

Number of Subjects (Planned and Enrolled)

-   Approximately 300 subjects were planned to be enrolled in this    study. A total of 315 subjects were enrolled.

Diagnosis and Main Criteria for Eligibility

-   Diagnosis/Subjects with signs and symptoms of dry eye disease

Key Inclusion Criteria:

Male or female subjects, at least 18 years of age, with a baseline(day 1) OSDI score of ≧18 and ≦65 (based on a 0 to 100 scale) wereeligible for enrollment. Subjects must have been using topicalophthalmic drops for dry eye at least twice daily, for at least 3 monthsprior to baseline, on average. If there was daily use of RESTASIS®Cyclosporine Ophthalmic Emulsion, it must have been in use for ≧6months. Three consecutive tear break-up time (TBUT) tests ≦10 seconds inat least 1 eye at baseline were required. Using the modified NationalEye Institute (NEI) Grid, all subjects had to have at least a Grade 1staining in at least 1 of the 5 zones of the cornea or in at least 1 ofthe 6 zones of the conjunctiva that is related to dry eye in at least 1eye at baseline.

Key Exclusion Criteria:

Key exclusion criteria included a Schirmer test (with anesthesia) ≦2 mmin either eye at baseline; corneal or conjunctival staining score of 5(modified NEI Grid) at baseline in any of the 5 corneal or 6conjunctival zones of either eye; use of systemic medications that couldhave affected a dry eye condition or vision, unless that medication hadbeen used at the same dose for at least 3 months prior to studyenrollment and the dosage was not expected to change during the courseof the study; history of anterior segment surgery or trauma that couldhave affected corneal sensitivity (eg, cataract surgery, laser-assistedin situ keratomileusis [LASIK], photorefractive keratectomy, or anysurgery involving a limbal or corneal incision) within 12 months priorto baseline; and current use of, and/or use within 2 weeks prior tobaseline, and/or likely use during the study period of any topicalophthalmic medications (eg, topical ophthalmic steroids, glaucoma drops,any topical cyclosporine product other than Restasis®. Subjects whodiscontinued use of daily Restasis® less than 3 months prior to baselinewere excluded from the study.

-   Duration of Treatment: The total duration of exposure to the study    product (drops) for each subject was 30 days. The visit schedule    consisted of a baseline visit (day 1) and 2 follow-up visits on days    7 (±3 days) and 30/early exit (±7 days).

Efficacy and Safety Measurements

-   Efficacy: Primary—OSDI questionnaire score-   Secondary—TBUT (with fluorescein), corneal staining (modified NEI    Grid, with fluorescein), conjunctival staining(modified NEI Grid,    with lissamine green), and Schirmer test (with anesthesia)

Other—Acceptability Questionnaire and Study Product Usage QuestionnaireSafety:

-   The safety measures were adverse events, biomicroscopy, and distance    visual acuity.

Statistical Methods:

The intent-to-treat (ITT) population consisted of all randomizedsubjects and was used for analyses of efficacy data based on thetreatment randomized. The safety population consisted of all treatedsubjects and was used for analyses of all safety data based on theactual treatment received. The per-protocol (PP) population consisted ofrandomized subjects who had no major protocol violations, as determinedprior to database lock.

The primary efficacy variable was the change from baseline in OSDI scoreat day 30 in the ITT population. The primary efficacy analysis wasperformed on the change from baseline in OSDI score at day 30 via a2-way analysis of variance (ANOVA) model with treatment and baselineOSDI stratification as the main effects.

Last observation carried forward (LOCF) was used to impute missing data.Noninferiority was tested using a 2-sided confidence interval (CI). Thetreatment difference and 95% CI in change from baseline in OSDI score atday 30 between NGE UD and OPTIVE UD (NGE UD minus OPTIVE UD) werecalculated based on the ANOVA model. Non-inferiority was established ifthe upper limit of the 95% CI was less than the prespecified margin of7.3.

The Secondary efficacy measures included TBUT, corneal staining,conjunctival staining, and Schirmer test. The raw values of thesemeasures were summarized for the ITT population, with missing dataimputation using LOCF at each scheduled follow-up visit. The treatmentdifference and 95% CI for between-treatment comparisons were calculated.The treatment differences and 95% CIs in change from baseline in OSDIscore at day 30 between NGE UD and NGE MD, NGE MD and OPTIVE MD werealso analyzed as secondary efficacy variables.

Acceptability was measured using the Acceptability Questionnaire, andproduct usage was measured using the Study Product Usage Questionnaire.Comparisons across groups were performed using ANOVA model withtreatment and baseline OSDI stratification as the main effects.

The safety variables included adverse events, biomicroscopy, anddistance visual acuity. Since both eyes were treated, both eyes wereincluded in the safety analyses. The Medical Dictionary for RegulatoryActivities (MedDRA) nomenclature was used to code adverse events. Thenumber and percent of subjects with clinically significant biomicroscopyfindings at one or more visits in either eye were tabulated. The overallfrequency distribution was analyzed using Pearson's chi-square test. Fora clinically significant biomicroscopic finding (more than 1 severitygrade increase [worsening] from baseline) with an incidence rate of ≧5%in any treatment group, the mean severity grade and the frequencydistribution of severity scores were summarized at each scheduled visit.

Data from the eye with the worst severity at the scheduled visit wastabulated. For distance visual acuity data, the total numbers of lettersread correctly were summarized based on the eye with worse change frombaseline at each scheduled visit. The frequency distribution wasanalyzed using Pearson's chi-square test.

A total of 315 subjects were enrolled in the study and included in theITT population; 105 subjects in the NGE UD group, 103 subjects in theOPTIVE UD group, 51 subjects in the NGE

MD group, and 56 subjects in the OPTIVE MD group. Overall, 310 (98.4%)subjects in the ITT population completed the study. Of the subjectsincluded in the per protocol population, 99.3% (303/305) completed thestudy whereas 98.4% (310/315) of the subjects in the safety populationcompleted the study. A total of 384 subjects were screened of which 69subjects were screen failures.

In the ITT population, the mean age of all subjects was 54.8 years(standard deviation 14.33) with 83.2% (262/315) of subjects in the >40years age group. In addition, 81.0% (255/315) of all subjects werefemale and 84.4% (266/315) were Caucasian.

Efficacy:

-   The primary efficacy endpoint was met. At day 30, no statistically    significant difference was observed between the NGE UD and the    OPTIVE UD groups in the mean change from baseline in OSDI score (95%    confidence interval [−5.42, 2.51]), in the ITT population. The NGE    UD formulation was noninferior to the OPTIVE UD formulation in    reducing the severity of symptoms of dryness as measured by the    change from baseline in OSDI score.-   Similar to the ITT population, there was no statistically    significant difference between the NGE UD and OPTIVE UD groups of    the PP population in the mean change from baseline in OSDI score at    day 30. The 95% confidence interval at the day 30 visit was (−5.72,    2.37); with an upper limit that is lower than the clinically    relevant margin of 7.3.-   In all 4 treatment groups, there was a statistically significant    difference (p<0.001) in the mean change from baseline in OSDI score    at the day 7 and day 30 visits for both the ITT and the PP    population.-   The NGE UD group was noninferior to the NGE MD group in the mean    change from baseline in OSDI score at day 30.-   The NGE UD group was noninferior to the OPTIVE UD and NGE MD groups    in the secondary efficacy measures of TBUT, corneal staining,    conjunctival staining, and Schirmer test.-   Overall, there were no statistically significant differences between    the NGE UD and OPTIVE UD groups, NGE UD and NGE MD groups, or NGE MD    and OPTIVE MD groups, in the mean values for each question of the    acceptability questionnaire at the day 7 and day 30 visits (except    for question 5 in the NGE MD versus OPTIVE MD comparison at day 7    and NGE UD versus NGE MD comparison at day 30), and in the mean    number of times per day that the study product was used during the    week prior to the day 7 and day 30 visits.

Safety:

-   At least 1 treatment-emergent adverse event (TEAE) of any causality    was reported in 11.4%, 15.5%, 13.7%,and 10.7% of subjects in the NGE    UD, OPTIVE UD, NGE MD and OPTIVE MD groups, respectively.-   No deaths were reported in the study. Two serious adverse events    were reported (bile duct stone [NGE UD group] and ankle fracture    [OPTIVE MD group]), none of which were treatment related in the    opinion of the investigator-   Overall 3 subjects discontinued from the study due to adverse    events, 1 subject each in the NGE UD, NGE MD and OPTIVE MD groups.-   Treatment-related TEAE were reported in 4.8%, 8.7%, 7.8%, and 5.4%    of subjects in the NGE UD, OPTIVE UD, NGE MD, and OPTIVE MD groups,    respectively. The most common treatment-related adverse events    (preferred terms) across treatment groups were instillation site    pain and vision blurred; NGE UD (3.8%, 2.9%), OPTIVE UD (3.9%,    2.9%), NGE MD (3.9%, 0.0%), and OPTIVE MD (3.6%, 1.8%).-   In the majority of the subjects, no change was observed in the    distance visual acuity at day 30 for all 4 treatment groups.

Conclusions

Efficacy: The results of this study demonstrate that the NGE UDformulation is non-inferior to the OPTIVE UD formulation in reducing theseverity of symptoms of dryness in subjects with mild to severe dry eye.

Safety: NGE UD appeared to be well tolerated during the study. The mostcommonly reported treatment-related adverse events were instillationsite pain and vision blurred. Throughout the study, there were notreatment-related serious adverse events. The safety profile wasconsistent with OPTIVE UD, OPTIVE MD, and NGE MD. This is supportive ofthe safety of the NGE UD formulation in clinical use, and confirms thesafety of the NGE MD formulation.

1. A composition useful as an artificial tear, which is a salt freeemulsion comprising castor oil and specifically excludes olive oil andcontains at least one active agent selected from the group consisting ofpolysorbate, carboxymethylcellulose and glycerine.
 2. The composition ofclaim 1 wherein said mixture comprises from 0.1% -0.5% w/w, castor oil.3. The composition of claim 2 wherein castor oil is the only oil in theemulsion.
 4. The composition of claim 3 wherein the castor oil isemulsified in an aqueous phase.
 5. The composition of claim 4 whereinthe castor oil is present in about 0.25% w/w.
 6. The composition ofclaim 5 further including a primary and a secondary emulsifier.
 7. Thecomposition of claims 5 wherein the composition contains a preservative.8. The composition of claim 7 wherein the preservative is selected fromthe group consisting of PURITE and benzalkonium chloride.
 9. Thecomposition of claim 8 wherein the preservative is Purite® is present ina concentration of about 0.01% w/v.
 10. An emulsion for use in treatingdry eye wherein the emulsion is salt-free and comprises castor oil,polysorbate 80, carboxymethylcellulose and glycerine.
 11. Thecomposition of claim 10 wherein the emulsion also contains theemulsifier pemulin.
 12. The emulsion of claim 11 further comprisingerythritol and levocarnitine.
 13. An emulsion for treating dry eye asshown in Table
 1. 14. A method of treating dry eye comprisingadministration of any one of the composition as shown in Table
 1. 15.The method of treating dry eye of claim 14 wherein the composition ispreservative free.
 16. The method of treating dry eye of claim 14wherein the method is applied at least once a day.
 17. The method oftreating dry eye claim 15 wherein the composition alleviates thesymptoms of dry eye syndrome.
 18. The method of claim 15 wherein thecomposition treats and prevents dry eye syndrome.